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MicroRNA Regulation of Embryonic Stem Cell Self-Renewal and Differentiation

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Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 695))

Abstract

Stem cell differentiation requires a complex coordination of events to transition from a self-renewing to a differentiated cell fate. Stem cells can be pluripotent (capable of giving rise to all embryonic lineages), multipotent (possessing the potential to give rise to multiple lineages) and unipotent (capable of given rise to a single cell lineage). Regardless of their potency all stem cells must silence their self-renewal program during differentiation. The self-renewal program can be defined as the integration of external and internal stimuli that enables a cell to proliferate while maintaining its potency. Two hallmarks of the self-renewal program are a self-reinforcing transcriptional network and a specialized cell-cycle profile. In this chapter we discuss the impact of various microRNAs (miRNAs) to either reinforce or inhibit the self-renewal program of stem cells and how this added regulatory layer provides robustness to cell-fate decisions. We will focus on embryonic stem cells (ESCs) describing miRNA function in self-renewal, differentiation and de-differentiation. We will compare and contrast miRNA functions in ESCs with miRNA function in lineage specific somatic stem cells and in cancer.

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References

  1. Surani MA, Hayashi K, Hajkova P. Genetic and epigenetic regulators of pluripotency. Cell 2007; 128(4):747–762.

    Article  CAS  PubMed  Google Scholar 

  2. Kriegstein A, Alvarez-Buylla A. The glial nature of embryonic and adult neural stem cells. Annu Rev Neurosci 2009; 32(1):149–184.

    Article  CAS  PubMed  Google Scholar 

  3. Mikkola HKA, Orkin SH. The journey of developing hematopoietic stem cells. Development 2006; 133(19):3733–3744.

    Article  CAS  PubMed  Google Scholar 

  4. Arai F, Suda T. Quiescent stem cells in the niche. In: StemBook, ed. The Stem Cell Research Community, StemBook, doi/10.3824/stembook.1.6.1, http://www.stembook.org. 2008.

    Google Scholar 

  5. Jaenisch R, Young R. Stem cells, the molecular circuitry of pluripotency and nuclear reprogramming. Cell 2008; 132(4):567–582.

    Article  CAS  PubMed  Google Scholar 

  6. Cai X, Hagedorn CH, Cullen BR. Human microRNAs are processed from capped, polyadenylated transcripts that can also function as mRNAs. RNA 2004; 10(12):1957–1966.

    Article  CAS  PubMed  Google Scholar 

  7. Lee Y, Kim M, Han J et al. MicroRNA genes are transcribed by RNA polymerase II. EMBO J 2004; 23(20):4051–4060.

    Article  CAS  PubMed  Google Scholar 

  8. Rodriguez A. Identification of mammalian microRNA host genes and transcription units. Genome Res 2004; 14(10a):1902–1910.

    Article  CAS  PubMed  Google Scholar 

  9. Basyuk E, Suavet F, Doglio A et al. Human let-7 stem-loop precursors harbor features of RNase III cleavage products. Nucleic Acids Res 2003; 31(22):6593–6597.

    Article  CAS  PubMed  Google Scholar 

  10. Gregory RI, Yan K, Amuthan G et al. The Microprocessor complex mediates the genesis of microRNAs. Nature 2004; 432(7014):235–240.

    Article  CAS  PubMed  Google Scholar 

  11. Lee Y, Ahn C, Han J et al. The nuclear RNase III Drosha initiates microRNA processing. Nature 2003; 425(6956):415–419.

    Article  CAS  PubMed  Google Scholar 

  12. Han J, Lee Y, Yeom K et al. The Drosha-DGCR8 complex in primary microRNA processing. Genes Dev 2004; 18(24):3016–3027.

    Article  CAS  PubMed  Google Scholar 

  13. Denli AM, Tops BBJ, Plasterk RHA et al. Processing of primary microRNAs by the Microprocessor complex. Nature 2004; 432(7014):231–235.

    Article  CAS  PubMed  Google Scholar 

  14. Han J, Lee Y, Yeom K et al. Molecular basis for the recognition of primary microRNAs by the drosha-DGCR8 complex. Cell 2006; 125(5):887–901.

    Article  CAS  PubMed  Google Scholar 

  15. Yi R, Qin Y, Macara IG et al. Exportin-5 mediates the nuclear export of premicroRNAs and short hairpin RNAs. Genes Dev 2003; 17(24):3011–3016.

    Article  CAS  PubMed  Google Scholar 

  16. Bohnsack MT, Czaplinski K, Gorlich D. Exportin 5 is a RanGTP-dependent dsRNA-binding protein that mediates nuclear export of premiRNAs. RNA 2004; 10(2):185–191.

    Article  CAS  PubMed  Google Scholar 

  17. Lund E, Güttinger S, Calado A et al. Nuclear export of microRNA precursors. Science 2004; 303(5654):95–98.

    Article  CAS  PubMed  Google Scholar 

  18. Hammond SM. Dicing and slicing: The core machinery of the RNA interference pathway. FEBS Letters 2005; 579(26):5822–5829.

    Article  CAS  PubMed  Google Scholar 

  19. Schwarz DS, Hutvágner G, Du T et al. Asymmetry in the assembly of the RNAi enzyme complex. Cell 2003; 115(2):199–208.

    Article  CAS  PubMed  Google Scholar 

  20. Bartel DP. MicroRNAs: Target recognition and regulatory functions. Cell 2009; 136(2):215–233.

    Article  CAS  PubMed  Google Scholar 

  21. Filipowicz W, Bhattacharyya SN, Sonenberg N. Mechanisms of posttranscriptional regulation by microRNAs: are the answers in sight? Nat Rev Genet 2008; 9(2):102–114.

    Article  CAS  PubMed  Google Scholar 

  22. Wang Y, Baskerville S, Shenoy A et al. Embryonic stem cell-specific microRNAs regulate the G1-S transition and promote rapid proliferation. Nat Genet 2008; 40(12):1478–1483.

    Article  CAS  PubMed  Google Scholar 

  23. Bar M, Wyman SK, Fritz BR et al. MicroRNA discovery and profiling in human embryonic stem cells by deep sequencing of small RNA libraries. Stem Cells 2008; 26(10):2496–2505.

    Article  CAS  PubMed  Google Scholar 

  24. Suh M, Lee Y, Kim JY et al. Human embryonic stem cells express a unique set of microRNAs. Dev Biol 2004; 270(2):488–498.

    Article  CAS  PubMed  Google Scholar 

  25. Kanellopoulou C, Muljo SA, Kung AL et al. Dicer-deficient mouse embryonic stem cells are defective in differentiation and centromeric silencing. Genes Dev 2005; 19(4):489–501.

    Article  CAS  PubMed  Google Scholar 

  26. Murchison EP, Partridge JF, Tam OH et al. Characterization of Dicer-deficient murine embryonic stem cells. Proc Natl Acad Sci USA 2005; 102(34):12135–12140.

    Article  CAS  PubMed  Google Scholar 

  27. Wang Y, Medvid R, Melton C et al. DGCR8 is essential for microRNA biogenesis and silencing of embryonic stem cell self-renewal. Nat Genet 2007; 39(3):380–385.

    Article  CAS  PubMed  Google Scholar 

  28. Savatier P, Huang S, Szekely L et al. Contrasting patterns of retinoblastoma protein expression in mouse embryonic stem cells and embryonic fibroblasts. Oncogene 1994; 9(3):809–818.

    CAS  PubMed  Google Scholar 

  29. Planas-Silva MD, Weinberg RA. The restriction point and control of cell proliferation. Curr Opin Cell Biol 1997; 9(6):768–772.

    Article  CAS  PubMed  Google Scholar 

  30. Giacinti C, Giordano A. RB and cell cycle progression. Oncogene 2006; 25(38):5220–5227.

    Article  CAS  PubMed  Google Scholar 

  31. Savatier P, Lapillonne H, van Grunsven LA et al. Withdrawal of differentiation inhibitory activity/leukemia inhibitory factor up-regulates D-type cyclins and cyclin-dependent kinase inhibitors in mouse embryonic stem cells. Oncogene 1996; 12(2):309–322.

    CAS  PubMed  Google Scholar 

  32. Mittnacht S. Control of pRB phosphorylation. Curr Opin Genet Dev 1998; 8(1):21–27.

    Article  CAS  PubMed  Google Scholar 

  33. Melton C, Judson R, Blelloch R. Opposing microRNA families regulate self-renewal in mouse embryonic stem cells. Nature 2010; Advance Online.

    Google Scholar 

  34. Singh AM, Dalton S. The cell cycle and Myc intersect with mechanisms that regulate pluripotency and reprogramming. Cell Stem Cell 2009; 5(2):141–149.

    Article  CAS  PubMed  Google Scholar 

  35. Cartwright P, McLean C, Sheppard A et al. LIF/STAT3 controls ES cell self-renewal and pluripotency by a Myc-dependent mechanism. Development 2005; 132(5):885–896.

    Article  CAS  PubMed  Google Scholar 

  36. Lin C, Jackson AL, Guo J et al. Myc-regulated microRNAs attenuate embryonic stem cell differentiation. EMBO J 2009; 28(20):3157–3170.

    Article  CAS  PubMed  Google Scholar 

  37. Benetti R, Gonzalo S, Jaco I et al. A mammalian microRNA cluster controls DNA methylation and telomere recombination via Rbl2-dependent regulation of DNA methyltransferases. Nat Struct Mol Biol 2008; 15(3):268–279.

    Article  CAS  PubMed  Google Scholar 

  38. Sinkkonen L, Hugenschmidt T, Berninger P et al. MicroRNAs control de novo DNA methylation through regulation of transcriptional repressors in mouse embryonic stem cells. Nat Struct Mol Biol 2008; 15(3):259–267.

    Article  CAS  PubMed  Google Scholar 

  39. Xu N, Papagiannakopoulos T, Pan G et al. MicroRNA-145 regulates OCT4, SOX2 and KLF4 and represses pluripotency in human embryonic stem cells. Cell 2009; 137(4):647–658.

    Article  CAS  PubMed  Google Scholar 

  40. Tay YM, Tam W, Ang Y et al. MicroRNA-134 modulates the differentiation of mouse embryonic stem cells, where it causes posttranscriptional attenuation of Nanog and LRH1. Stem Cells 2008; 26(1):17–29.

    Article  CAS  PubMed  Google Scholar 

  41. Tay Y, Zhang J, Thomson AM et al. MicroRNAs to Nanog, Oct4 and Sox2 coding regions modulate embryonic stem cell differentiation. Nature 2008; 455(7216):1124–1128.

    Article  CAS  PubMed  Google Scholar 

  42. Johnson CD, Esquela-Kerscher A, Stefani G et al. The let-7 microRNA represses cell proliferation pathways in human cells. Cancer Res 2007; 67(16):7713–7722.

    Article  CAS  PubMed  Google Scholar 

  43. Kumar MS, Erkeland SJ, Pester RE et al. Suppression of nonsmall cell lung tumor development by the let-7 microRNA family. Proc Natl Acad Sci USA 2008; 105(10):3903–3908.

    Article  CAS  PubMed  Google Scholar 

  44. Schultz J, Lorenz P, Gross G et al. MicroRNA let-7b targets important cell cycle molecules in malignant melanoma cells and interferes with anchorage-independent growth. Cell Res 2008; 18(5):549–557.

    Article  CAS  PubMed  Google Scholar 

  45. Reinhart BJ, Slack FJ, Basson M et al. The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans. Nature 2000; 403(6772):901–906.

    Article  CAS  PubMed  Google Scholar 

  46. Pasquinelli AE, Reinhart BJ, Slack F et al. Conservation of the sequence and temporal expression of let-7 heterochronic regulatory RNA. Nature 2000; 408(6808):86–89.

    Article  CAS  PubMed  Google Scholar 

  47. Landgraf P, Rusu M, Sheridan R et al. A mammalian microRNA expression atlas based on small RNA library sequencing. Cell 2007; 129(7):1401–1414.

    Article  CAS  PubMed  Google Scholar 

  48. Griffiths-Jones S. The microRNA Registry. Nucl Acids Res 2004; 32(suppl 1):D109–111.

    Article  CAS  PubMed  Google Scholar 

  49. Griffiths-Jones S, Grocock RJ, van Dongen S et al. miRBase: microRNA sequences, targets and gene nomenclature. Nucl Acids Res 2006; 1;34(Database issue):D140-4

    Google Scholar 

  50. Griffiths-Jones S, Saini HK, van Dongen S et al. miRBase: tools for microRNA genomics. Nucl Acids Res 2008; 36(suppl_1):D154–158.

    CAS  PubMed  Google Scholar 

  51. Hagan JP, Piskounova E, Gregory RI. Lin28 recruits the TUTase Zcchc11 to inhibit let-7 maturation in mouse embryonic stem cells. Nat Struct Mol Biol 2009; 16(10):1021–1025.

    Article  CAS  PubMed  Google Scholar 

  52. Heo I, Joo C, Cho J et al. Lin28 mediates the terminal uridylation of let-7 precursor MicroRNA. Mol Cell 2008; 32(2):276–84.

    Article  CAS  PubMed  Google Scholar 

  53. Heo I, Joo C, Kim Y et al. TUT4 in concert with Lin28 suppresses microRNA biogenesis through premicroRNA uridylation. Cell 2009; 138(4):696–708.

    Article  CAS  PubMed  Google Scholar 

  54. Rybak A, Fuchs H, Smirnova L et al. A feedback loop comprising lin-28 and let-7 controls prelet-7 maturation during neural stem-cell commitment. Nat Cell Biol 2008; 10(8):987–93.

    Article  CAS  PubMed  Google Scholar 

  55. Thomson JM, Newman M, Parker JS et al. Extensive posttranscriptional regulation of microRNAs and its implications for cancer. Genes Dev 2006; 20(16):2202–7.

    Article  CAS  PubMed  Google Scholar 

  56. Viswanathan SR, Daley GQ, Gregory RI. Selective blockade of microRNA processing by Lin28. Science 2008; 320(5872):97–100.

    Article  CAS  PubMed  Google Scholar 

  57. Wu L, Belasco JG. Micro-RNA regulation of the mammalian lin-28 gene during neuronal differentiation of embryonal carcinoma cells. Mol Cell Biol 2005; 25(21):9198–9208.

    Article  CAS  PubMed  Google Scholar 

  58. Yang D, Moss EG. Temporally regulated expression of Lin-28 in diverse tissues of the developing mouse. Gene Expression Patterns 2003; 3(6):719–726.

    Article  CAS  PubMed  Google Scholar 

  59. Marson A, Levine SS, Cole MF et al. Connecting microRNA genes to the core transcriptional regulatory circuitry of embryonic stem cells. Cell 2008; 134(3):521–533.

    Article  CAS  PubMed  Google Scholar 

  60. Burdon T, Smith A, Savatier P. Signalling, cell cycle and pluripotency in embryonic stem cells. Trends Cell Biol 2002; 12(9):432–438.

    Article  CAS  PubMed  Google Scholar 

  61. Judson RL, Babiarz JE, Venere M et al. Embryonic stem cell-specific microRNAs promote induced pluripotency. Nat Biotechnol 2009; 27(5):459–461.

    Article  CAS  PubMed  Google Scholar 

  62. Schwamborn JC, Berezikov E, Knoblich JA. The TRIM-NHL Protein TRIM32 activates microRNAs and prevents self-renewal in mouse neural progenitors. Cell 2009; 136(5):913–925.

    Article  CAS  PubMed  Google Scholar 

  63. Maller Schulman BR, Liang X, Stahlhut C et al. The let-7 microRNA target gene, Mlin41/Trim71 is required for mouse embryonic survival and neural tube closure. Cell Cycle 2008; 7(24):3935–3942.

    Google Scholar 

  64. Rybak A, Fuchs H, Hadian K et al. The let-7 target gene mouse lin-41 is a stem cell specific E3 ubiquitin ligase for the miRNA pathway protein Ago2. Nat Cell Biol 2009; 11(12):1411–1420.

    Article  CAS  PubMed  Google Scholar 

  65. Neumuller RA, Betschinger J, Fischer A et al. Mei-P26 regulates microRNAs and cell growth in the Drosophila ovarian stem cell lineage. Nature 2008; 454(7201):241–245.

    Article  PubMed  Google Scholar 

  66. Hochedlinger K, Plath K. Epigenetic reprogramming and induced pluripotency. Development 2009; 136(4):509–523.

    Article  CAS  PubMed  Google Scholar 

  67. Kumar MS, Lu J, Mercer KL et al. Impaired microRNA processing enhances cellular transformation and tumorigenesis. Nat Genet 2007; 39(5):673–677.

    Article  CAS  PubMed  Google Scholar 

  68. Ivanovska I, Ball AS, Diaz RL et al. MicroRNAs in the miR-106b Family Regulate p21/CDKN1A and Promote Cell Cycle Progression. Mol Cell Biol 2008; 28(7):2167–2174.

    Article  CAS  PubMed  Google Scholar 

  69. Petrocca F, Visone R, Onelli MR et al. E2F1-Regulated microRNAs impair TGF[beta]-dependent cell-cycle arrest and apoptosis in gastric cancer. Cancer Cell 2008; 13(3):272–286.

    Article  CAS  PubMed  Google Scholar 

  70. He L, Thomson JM, Hemann MT et al. A microRNA polycistron as a potential human oncogene. Nature 2005; 435(7043):828–833.

    Article  CAS  PubMed  Google Scholar 

  71. Mendell JT. miRiad roles for the miR-17-92 cluster in development and disease. Cell 2008; 133(2):217–222.

    Article  CAS  PubMed  Google Scholar 

  72. Dews M, Homayouni A, Yu D et al. Augmentation of tumor angiogenesis by a Myc-activated microRNA cluster. Nat Genet 2006; 38(9):1060–1065.

    Article  CAS  PubMed  Google Scholar 

  73. Voorhoeve PM, le Sage C, Schrier M et al. A genetic screen implicates miRNA-372 and miRNA-373 as oncogenes in testicular germ cell tumors. Cell 2006; 124(6):1169–1181.

    Article  CAS  PubMed  Google Scholar 

  74. Yu F, Yao H, Zhu P et al. let-7 regulates self renewal and tumorigenicity of breast cancer cells. Cell 2007; 131:1109–1123.

    Article  CAS  PubMed  Google Scholar 

  75. Trang P, Medina PP, Wiggins JF et al. Regression of murine lung tumors by the let-7 microRNA. Oncogene [Internet] 2009 [cited 2009 Dec 16]; Available from: http://www.ncbi.nlm.nih.gov/pubmed/19966857.

    Google Scholar 

  76. Kumar MS, Erkeland SJ, Pester RE et al. Suppression of nonsmall cell lung tumor development by the let-7 microRNA family. Proc Natl Acad Sci USA 2008; 105(10):3903–3908.

    Article  CAS  PubMed  Google Scholar 

  77. Esquela-Kerscher A, Trang P, Wiggins JF et al. The let-7 microRNA reduces tumor growth in mouse models of lung cancer. Cell Cycle 2008; 7(6):759–764.

    Article  CAS  PubMed  Google Scholar 

  78. Chang T, Zeitels LR, Hwang H et al. Lin-28B transactivation is necessary for Myc-mediated let-7 repression and proliferation. Proc Natl Acad Sci USA 2009; 106(9):3384–3389.

    Article  CAS  PubMed  Google Scholar 

  79. Iliopoulos D, Hirsch HA, Struhl K. An epigenetic switch involving NF-kappaB, Lin28, Let-7 MicroRNA and IL6 links inflammation to cell transformation. Cell 2009; 139(4):693–706.

    Article  CAS  PubMed  Google Scholar 

  80. Viswanathan SR, Powers JT, Einhorn W et al. Lin28 promotes transformation and is associated with advanced human malignancies. Nat Genet 2009; 41(7):843–848.

    Article  CAS  PubMed  Google Scholar 

  81. Dangi-Garimella S, Yun J, Eves EM et al. Raf kinase inhibitory protein suppresses a metastasis signalling cascade involving LIN28 and let-7. EMBO J 2009; 28(4):347–358.

    Article  CAS  PubMed  Google Scholar 

  82. Büssing I, Slack FJ, Großhans H. let-7 microRNAs in development, stem cells and cancer. Trends Mol Med 2008; 14(9):400–409.

    Article  PubMed  Google Scholar 

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Correspondence to Robert Blelloch .

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Melton, C., Blelloch, R. (2010). MicroRNA Regulation of Embryonic Stem Cell Self-Renewal and Differentiation. In: Meshorer, E., Plath, K. (eds) The Cell Biology of Stem Cells. Advances in Experimental Medicine and Biology, vol 695. Springer, Boston, MA. https://doi.org/10.1007/978-1-4419-7037-4_8

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